基于三维细胞的人参皂苷20(S)-Rh2干预抗肿瘤药物靶向转运动力学及代谢性分子机制研究

Solid tumors have complex microenvironment, difficult to drug penetration and easy to drug resistance. All this characteristics lead to antitumor drugs difficult to interaction with target to play antitumor effect. But, it is not clear that how antitumor drugs across these barriers to reach the target inside the solid tumor and how chemotherapeutic agents play a synergistic role in this process. By metabolomics-informed investigation, selecting adriamycin as model drug and breast cancer as model disease, we construct the double 3D targeted transport kinetics evaluation system of antitumor drugs based on multicellular layers and multicellular spheroids. As a potent inhibitor of P-gp, we investigate the effect of 20(S)-Ginsenoside-Rh2 on 3D targeted transport kinetics of adriamycin. Finally, we elucidate the metabolic molecular mechanism by association analysis of metabolic pathway and molecular signaling pathway. This project achieve the breakthroughs of cell pharmacokinetics study from 2D to 3D, improve the kinetics evaluation system of antitumor drugs, promote the accuracy of in vitro to predict in vivo, provide new methods to screen chemotherapeutic agents in vitro and offer technical support for finding new sensitized targets.

实体瘤具有复杂的微环境、药物难穿透、易产生耐药等特点导致抗肿瘤药物很难到达靶点发挥药效。然而抗肿瘤药物是如何跨过这些屏障到达实体瘤内靶点发挥作用、化疗增敏剂如何在这一进程中起到增效作用的机制并不明确。本项目以代谢组学为导向，选取阿霉素为模型药物，乳腺癌为模型疾病，拟构建基于多层细胞和多细胞球体的双重抗肿瘤药物三维靶向转运动力学评价体系，研究人参皂苷20(S)-Rh2作为P-gp的有效抑制剂在3D细胞上干预ADR靶向转运动力学的规律，最后整合代谢通路和分子信号通路的关联分析，阐明20(S)-Rh2干预ADR 3D靶向转运的代谢性分子机制。实现了细胞药代动力学研究从“二维”到“三维”的技术突破，完善了抗肿瘤药物动力学评价体系，提高体外预测体内的准确度，为体外化疗增敏剂的筛选提供新方法，为寻找新的增敏靶点提供技术支撑。

实体瘤具有复杂的微环境、药物难穿透、易产生耐药等特点导致抗肿瘤药物很难到达靶点发挥药效。然而抗肿瘤药物是如何跨过这些屏障到达实体瘤内靶点发挥作用、化疗增敏剂如何在这一进程中起到增效作用的机制并不明确。我们可以通过血浆内的药物经时过程来整体评价药物在体内的宏观过程，可以通过胞内的摄取和亚细胞的再分布等来评价药物在细胞内的微观过程，而组织水平是桥接上述二者的关键，并且药物在实体瘤内的靶向转运直接决定了实体瘤各区域细胞外的药物供应量。因此，促进抗肿瘤药物的瘤内靶向转运也是改善疗效的关键步骤。本项目以代谢组学为导向，选取阿霉素为模型药物，乳腺癌为模型疾病，拟构建基于多层细胞和多细胞球体的双重抗肿瘤药物三维靶向转运动力学评价体系，研究人参皂苷20(S)-Rh2作为P-gp的有效抑制剂在3D细胞上干预ADR靶向转运动力学的规律，最后整合代谢通路和分子信号通路的关联分析，阐明20(S)-Rh2干预ADR 3D靶向转运的代谢性分子机制。实现了细胞药代动力学研究从“二维”到“三维”的技术突破，完善了抗肿瘤药物动力学评价体系，提高体外预测体内的准确度，为体外化疗增敏剂的筛选提供新方法，为寻找新的增敏靶点提供技术支撑。